Summary The long-term goal of this research project is to understand the mechanism governing the central control of energy balance. Three ligand-receptor pairs have been shown to play a key role in the regulation of energy balance, as deficits in any of these three signaling pathways lead to severe obesity in humans and mice. They are leptin and leptin receptor, alpha-melanocyte-stimulating hormone and melanocortin-4 receptor (MC4R), and brain-derived neurotrophic factor (BDNF) and its receptor TrkB. Great progress has been made in understanding the neural mechanism by which the first two ligand-receptor pairs regulate energy balance. However, very little is known on how the BDNF-TrkB pathway regulates energy balance. Our preliminary studies found that deletion of the TrkB gene in the paraventricular hypothalamus (PVH) caused extreme hyperphagia and severe obesity and that TrkB deletion in the dorsomedial hypothalamus (DMH) led to modest hyperphagia, impaired thermogenesis, reduced locomotor activity, and obesity. These exciting observations lead us to posit that some neural circuits linked to PVHTrkB and DMHTrkB neurons play a key role in regulating appetite and energy expenditure. We propose to demonstrate an important role for PVHTrkB and DMHTrkB neurons in the control of energy balance by deleting the TrkB gene in the PVH and DMH and by activating TrkB neurons in these two nuclei with the DREADD technology, to identify the neural circuits that mediate the effect of TrkB expressed in the PVH and DMH on appetite and energy expenditure using viral tract tracing and projection-specific gene deletion, and to characterize PVHTrkB and DMHTrkB neurons through gene expression profiling.